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A Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of SAR443820 in adult participants with amyotrophic lateral sclerosis, followed by an open-label extension

Phase 2 study for SAR443820 in participants with amyotrophic lateral sclerosis (ALS)
(HIMALAYA)

305

The mean (standard deviation [SD]) age of the randomized population was 56.9 (11.5) years, 28.9% of the population was 65 years or older. A total of 183 (60.0%) male and 122 (40.0%) female participants were included in the study, most of them were White (195 [63.9%] participants) or Asian (78 [25.6%] participants). The mean (SD) baseline Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) total score was 36.06 (4.61) overall (range: 21.0 to 45.0).

- Randomized: 305 (SAR443820: 203, Placebo: 102) - Treated: 304 (SAR443820: 202, Placebo: 102) - Treatment completed in Part A: 242 (SAR443820: 155, Placebo: 87) - Treatment permanently discontinued in Part A: 62 (SAR443820: 47, Placebo: 15) - Completed study Part A: 255 (SAR443820: 167, Placebo: 88) - Discontinued from study Part A: 50 (SAR443820: 36, Placebo: 14) - Entered study Part B regardless of treatment: 255 (SAR443820: 167, Placebo: 88) - Entered Part B with treatment: 215 (SAR443820: 136, Placebo: 79) - Treatment permanently discontinued in Part B: 215 (SAR443820: 136, Placebo: 79) - Discontinued from study Part B: 255 (SAR443820: 167, Placebo: 88)

Part A: - TEAEs: the percentage of participants with any TEAEs was higher in the SAR443820 group (171 [84.7%]) compared with the placebo group (80 [78.4%]). - - TEAEs were assessed as related to the investigational medicinal product (by the Investigator) in a greater proportion of participants in SAR443820 group (73 [36.1%]) when compared to placebo group (19 [18.6%]). - - The 4 most frequently reported TEAEs in either intervention group by Preferred Term (PT) were: fall (44 [21.8%] participants in the SAR443820 group and 22 [21.6%] participants in the placebo group) (hereinafter in the same group order), hepatic enzyme increased (35 [17.3%], 2 [2.0%]), headache (25 [12.4%], 9 [8.8%]), and COVID-19 (21 [10.4%], 11 [10.8%]). - - The PT with notably higher TEAE incidence in the SAR443820 group compared with placebo group (with a difference of >=5%) was hepatic enzyme increased (35 [17.3%], 2 [2.0%]). - SAEs: The incidence of treatment-emergent SAEs was similar in both the SAR443820 group (32 [15.8%]) and the placebo group (16 [15.7%]). - - Treatment-emergent SAEs were assessed as related to the investigational medicinal product in 4 (2.0%) and 0 participants in the SAR443820 group and in the placebo group, respectively (3 [1.5%] participants with hepatic enzyme increased and 1 [0.5%] participant with drug-induced liver injury [DILI]). - Deaths: A total of 9 participants died during Part A (7 [3.5%] and 2 [2.0%] participants in the SAR443820 group and in the placebo group, respectively), in similar proportions across groups. - TEAEs leading to permanent treatment discontinuation: TEAEs leading to permanent treatment discontinuation were reported with higher incidence in the SAR443820 group than in the placebo group (28 [13.9%] and 5 [4.9%] participants, respectively). - - The most frequently reported TEAEs leading to permanent treatment discontinuation (in >=2% of participants in either intervention group) at the PT level were hepatic enzyme increased (16 [7.9%] participants in the SAR443820 group and 1 [1.0%] participants in the placebo group). Part A + Part B (while on SAR443820): For Part A + Part B safety, results are displayed "while on SAR443820" cumulatively from the beginning of the study to the end of Part B by the time of database lock. They include participants who started receiving SAR443820 in Part A from the SAR443820/SAR443820 group as well as participants who switched to SAR443820 in Part B from the placebo/SAR443820 group. - TEAEs: the percentage of participants with any TEAEs was higher in the SAR443820/SAR443820 group (183 [90.6%]) compared with the placebo/SAR443820 group (51 [64.6%]). - - The incidence of TEAEs considered to be related to investigational medicinal product (as per Investigator) was higher in the SAR443820/SAR443820 group (83 [41.1%]) compared with placebo/SAR443820 group (23 [29.1%]). - - The 4 most frequently reported TEAEs in either intervention group by PT were: fall (53 [26.2%] participants in the SAR443820/SAR443820 group and 10 [12.7%] participants in the placebo/SAR443820 group) (hereinafter in the same group order), hepatic enzyme increased (41 [20.3%], 13 [16.5%]), headache (26 [12.9%], 3 [3.8%]), and COVID-19 (24 [11.9%], 3 [3.8%]). - - The PTs with notably higher TEAE incidence in the SAR443820/SAR443820 group compared with placebo/SAR443820 group (with a difference of >=5%) were fall (see above), headache (see above), diarrhoea (20 [9.9%] versus 1 [1.3%]), COVID-19 (see above), respiratory failure (15 [7.4%] versus no participants), dizziness (14 [6.9%] versus 1 [1.3%]), and fatigue (10 [5.0%] versus no participants). - SAEs: treatment-emergent SAEs were reported in 66 (23.5%) participants, with higher incidence in the SAR443820/SAR443820 group (53 [26.2%]) compared with placebo/SAR443820 group (13 [16.5%]). - - Treatment-emergent SAEs were assessed as related to the investigational medicinal product in 4 (2.0%) and 5 (6.3%) participants in the SAR443820/SAR443820 group and in the placebo/SAR443820 group, respectively: in SAR443820/SAR443820, 3 (1.5%) participants with hepatic enzyme increased and 1 (0.5%) with DILI. In placebo/SAR443820 group, 3 (3.8%) participants with hepatic enzyme increased, 1 (1.3%) with gastrointestinal infection, and 1 (1.3%) with urinary tract infection. - Deaths: A total of 35 deaths occurred regardless of the study period: In Part A + Part B, a total of 16 deaths were reported (14 [6.9%] in the SAR443820/SAR443820 group and 2 [2.5%] in the placebo/SAR443820 group). Post-treatment, 9 (4.5%) deaths in the SAR443820 group and 10 (9.8%) in the placebo group were reported. Only one SAE resulting in death was assessed as related to the investigational medicinal product, which was a gastrointestinal infection in a participant from the placebo/SAR443820 group. - TEAEs leading to permanent treatment discontinuation: TEAEs leading to permanent treatment discontinuation (while on treatment) were reported in 46 (16.4%) participants overall, with higher incidence in the SAR443820/SAR443820 group (36 [17.8%]) compared with placebo/SAR443820 group (10 [12.7%]). - - The most frequently reported TEAEs leading to permanent treatment discontinuation (in >=2% of participants in either intervention group) at the PT level were: hepatic enzyme increased (18 [8.9%] participants in the SAR443820/SAR443820 group and 7 [8.9%] participants in the placebo/SAR443820 group) (hereinafter in the same group order), and respiratory failure (4 [2.0%], no participants).

Part A Primary endpoint: The primary endpoint was not met: Mean (SD) changes from baseline in ALSFRS-R at Week 24 were similar in both the SAR443820 and the placebo groups (-6.1 [5.4] and -5.9 [5.9], respectively). No significant difference was found in least squares (LS) mean (95% confidence interval [CI]) between the SAR443820 group (-6.730 [-7.484, -5.976]) and the placebo group (-6.317 [-7.362, -5.271]) (P=0.5289). Secondary endpoints At Week 24: - The mean (SD) CAFS scores were similar in the SAR443820 group (147.13 [83.06]) and in the placebo group (151.19 [90.71]). - The mean (SD) SVC had decreased when compared to baseline. This decrease was similar in both groups (-11.24 [13.35] and -13.43 [14.66] in the SAR443820 group and in the placebo group, respectively). Also, no difference was found in LS mean (95% CI) between the SAR443820 group (-13.163 [-15.215, -11.112]) and the placebo group (-13.583 [-16.376, -10.790]). - The mean (SD) in megascore (pertaining to muscle strength) had slightly decreased since baseline. The decrease was found similar for both groups and mean (SD) change from baseline was -0.495 (0.704) in the SAR443820 group and -0.498 (0.960) in the placebo group. In addition, no difference was found in LS mean (95% CI) between the SAR443820 group (-0.519 [-0.632, -0.406]) and the placebo group (-0.514 [-0.664, -0.365]). - There was a slight increase in ALSAQ-5 score, for both groups, and mean (SD) change from baseline was similar in the SAR443820 group (2.4 [3.1]) and in the placebo group (2.1 [3.1]). No difference was found in LS mean (95% CI) between the SAR443820 group (2.546 [2.057, 3.035]) and the placebo group (2.026 [1.358, 2.695]). - Mean (SD) changes from baseline to Week 24 in serum NfL were similar in the SAR443820 group (0.362 pg/mL [22.244 pg/mL]) and in the placebo group (0.682 pg/mL [39.923 pg/mL]). No difference was found in Week 24 LS geometric mean ratio to baseline (95% CI) between the SAR443820 group (0.994 [0.955, 1.034]) and the placebo group (1.035 [0.981, 1.092]). Part B: Cumulative Part A + Part B data, up to data lock point, did not reveal any difference in efficacy related primary (CAFS at Week 52: mean rank = 89.99 and 90.02 for SAR443820/SAR443820 and placebo/SAR443820, respectively) and secondary endpoints between SAR443820/SAR443820 group and placebo/SAR443820 group.

A total of 305 participants were randomized in Part A; of these, 304 were treated (202 in the SAR443820 group and 102 in the placebo group). The primary objective of the study was not met, as there was no significant difference in the primary endpoint between the SAR443820 and placebo groups. Safety findings included a higher incidence of TEAEs in the SAR443820 group, particularly hepatic enzyme increases, and a higher rate of permanent treatment discontinuation due to TEAEs compared to the placebo group.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220078

Dr. Richard Tsai

Denali Therapeutics Inc.

161 Oyster Point Boulevard, South San Francisco, CA 94080 USA

clinical-trials-disclosures@dnli.com

Clinical Trials Disclosures Group

Denali Therapeutics Inc.

161 Oyster Point Boulevard, South San Francisco, CA 94080 USA

+1 650 580 1167

clinical-trials-disclosures@dnli.com

Complete

May. 24, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Diagnosis of possible, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria
- Time since onset of first symptom of ALS <=2 years.
- Slow Vital Capacity (SVC) >=60% of the predicted value.
- Be able to swallow the study tablets at the screening visit.
- Either not currently receiving riluzole or on a stable dose of riluzole for at least 4 weeks before the screening visit. Participants receiving riluzole are expected to remain on the same dose throughout the duration of the study.
- Either not currently receiving edaravone or on the approved standard schedule of edaravone treatment. Participants receiving edaravone must have completed at least 1 cycle of treatment before the screening visit and are expected to continue edaravone treatment throughout the duration of the study.
- Either not currently receiving the combination of sodium phenylbutyrate and taurursodiol or on the approved standard schedule of the combination of sodium phenylbutyrate and taurursodiol treatment for at least 4 weeks before the screening visit. Participants receiving the combination of sodium phenylbutyrate and taurursodiol are expected to remain on the approved standard schedule throughout the duration of the study.
- Participants with a body weight no less than 45 kg and body mass index no less than 18 kg/m^2 at the screening visit.
- Female participants with childbearing potential are eligible to participate if they are not pregnant or breastfeeding and agree to use adequate contraceptive method during study intervention period and for at least 32 days after the last dose of study drug.
- Male participants must agree to use highly effective contraceptive method during the study period and for at least 92 days following their last dose of the study drug. Male participants must not donate sperms for the duration of study and 92 days after last dose of study drug.

- A history of seizure (History of febrile seizure during childhood is allowed).
- Having central IV lines, such as a peripherally inserted central catheter (PICC) or midline or port-a-cath lines.
- With significant cognitive impairment, psychiatric disease, other neurodegenerative disorder (eg, Parkinson disease or AD), substance abuse, other causes of neuromuscular weakness, or any other condition that would make the participants unsuitable for participating in the study or could interfere with assessment or completing the study in the opinion of the Investigator.
- History of recent serious infection (eg, pneumonia, septicemia) within 4 weeks of the screening visit; infection requiring hospitalization or treatment with IV antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infection (such as tuberculosis) deemed unacceptable as per the Investigator's judgment.
- With active herpes zoster infection within 2 months prior to the screening visit.
- A documented history of attempted suicide within 6 months prior to the screening visit, present with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS), or in the Investigator's judgment are at risk for a suicide attempt.
- History of unstable or severe cardiac, pulmonary, oncological, hepatic, or renal disease or another medically significant illness other than ALS precluding their safe participation in this study.
- Participants who are pregnant or are currently breastfeeding.
- A known history of allergy to any ingredients of SAR443820.
- Currently or previously treated with any strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers listed in Appendix 10 of the protocol within the specified washout period before the screening visit.
- Received a live vaccine within 14 days before the screening visit.
- Participants with concurrent participation in any other interventional clinical study or who have received treatment with another investigational drug (eg sodium phenylbutyrate or taurursodiol) within 4 weeks or 5 half-lives of the investigational agent before the screening visit, whichever is longer.
- Participants who have received stem cell or gene therapy for ALS at any time in the past.
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0 x upper limit of normal (ULN)
- Bilirubin >1.5 x ULN unless the participant has documented Gilbert syndrome (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)
- Serum albumin <3.5 g/dL
- Estimated glomerular filtration rate <60 mL/min/1.73 m^2 (Modification of Diet in Renal Disease [MDRD])

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Both

Amyotrophic lateral sclerosis

Drug: SAR443820
Pharmaceutical form: Tablet, Route of administration: Oral
Drug: Placebo
Pharmaceutical form: Tablet, Route of administration: Oral

1. Change from baseline in the ALSFRS-R total score -Part A [ Time Frame: From baseline to Week 24 ]
2. Combined assessment of the function and survival (CAFS) score -Part B [ Time Frame: Week 52 ]

1. Combined assessment of the function and survival (CAFS) score -Part A [ Time Frame: Week 24 ]
2. Change from baseline in slow vital capacity (SVC) -Part A [ Time Frame: From baseline to Week 24 ]
3. Muscle Strength - Part A [ Time Frame: From baseline to Week 24 ]
Measured using a grip dynamometer and a handheld dynamometer (HHD)
4. Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ5) -Part A [ Time Frame: From baseline to Week 24 ]
5. Change from baseline in serum neurofilament light chain (NfL) -Part A [ Time Frame: From baseline to Week 24 ]
6. Number of patients with treatment emergent adverse events (TEAE) and Serious adverse event (SAE) - Part A [ Time Frame: Up to Week 24 ]
7. Assessment of pharmacokinetic parameter, Plasma concentration of SAR443820 -Part A [ Time Frame: Day 1, Week 2, Week 8 ]
8. Combined assessment of the function and survival (CAFS) score - Part B [ Time Frame: Week 76, Week 104 ]
9. Change from baseline in the ALSFRS-R total score-Part B [ Time Frame: From baseline to Week 52 and Week 76 and Week 104 ]
10. Time from baseline to the occurrence of either death, or permanent assisted ventilation (>22 hours daily for >7 consecutive days), whichever comes first - Part B [ Time Frame: Up to Week 106 ]
11. Time from baseline to the occurrence of death-Part B [ Time Frame: Up to Week 106 ]
12. Change from baseline in slow vital capacity (SVC)-Part B [ Time Frame: From baseline to Week 52, Week 76 and Week 104 ]
13. Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5)-Part B [ Time Frame: From baseline to Week 52, Week 76 and Week 104 ]
14. Change from baseline in serum neurofilament light chain (NfL)-Part B [ Time Frame: Week 52 ]
15. Number of patients with treatment emergent adverse events (TEAE) and Serious adverse event (SAE) -Part B [ Time Frame: Up to Week 106 ]
16. Assessment of pharmacokinetic parameter, Plasma concentration of SAR443820 -Part B [ Time Frame: Week 28 ]

April. 18, 2022

Belgium/Canada/France/Germany/Netherlands/United Kingdom/United States/China/Italy/Poland/Spain/Sweden